Interactions of the placenta and the maternal immune system are likely to be critical in the establishment of pregnancy, and in particular the uterine immune environment may influence trophoblast differentiation, placental growth, and invasion of the maternal endometrium. Inappropriate development/regulation of these activities has enormous potential to contribute to placental dysfunction and maternal and fetal morbidity and mortality. We have recently demonstrated that the rhesus monkey placenta expresses a novel MHC class I locus, designated Mamu-AG, which has significant biochemical and molecular similarities to the human placental MHC class I molecular HLA-G. Although HLA-G is hypothesized to mediate maternal-fetal immune tolerance via interaction with maternal uterine natural killer (NK) cells, functional in vivo studies of the role(s) of placental MHC class I molecules in normal implantation and establishment and maintenance of pregnancy are not possible in a clinical setting. We hypothesize that Mamu-AG inhibits uterine and peripheral blood NK cell activity in the rhesus monkey via interactions with specific killer inhibitory receptors on NK cell membranes. In order to begin to test this hypothesis, we propose three specific aims: Specific Aim 1 is to generate Mamu-AG-specific monoclonal antibodies and to define the distribution of this MHC class I molecule in adult and fetal rhesus monkeys. Specific Aim 2 is to use anti-Mamu AG antibodies with both in vitro culture systems and in vivo passive immunization studies to explore the role of Mamu-AG in trophoblast-NK cell interactions and trophoblast differentiation. Specific Aim 3 is to clone natural killer inhibitory receptors (KIRs) of the trophoblast differentiation. Specific Aim 3 is to clone natural killer inhibitory receptors (KIRs) of the immunoglobulin (Ig) and C-type lectin superfamilies expressed in the rhesus monkey and characterize activity of the peripheral and decidual NK cells against trophoblast and non-trophoblast targets. These aims build on our previous studies which establish the rhesus monkey as a model for studying human maternal-fetal immune tolerance. The modulation of trophoblast-NK cell interactions in vivo will not only provide insights into maternal-fetal immune tolerance. The modulation of trophoblast-NK cell interactions in vivo will not only provide insights into maternal-fetal dialogue and placental biology, but will also advance the use of the primate model to study NK cell biology, relevant to the setting of infection as well as immune tolerance.